Atrial fibrillation (AF) is the most common cause of arrhythmias in the elderly; it has an incidence of more than 5 percent in people > 69 years of age. At present, there is no satisfactory treatment of this disease. The ChanTest Phase I SBIR was directed towards the discovery of novel drugs for this disease and in these experiments, the investigators identified a substituted piperidine compound that promises to be an effective antiarrhythmic agent. They found that this drug blocks the hERG/IKr current at low nanomolar concentrations, yet does not prolong the action potential duration in canine Purkinje fibers at micromolar concentrations as might be expected. The investigators hypothesized that the drug also blocked cardiac Na and Ca currents at nanomolar concentrations and, as a result, the hERG/IKr block was offset and there was no change in action potential duration. The drug had another useful characteristic, namely the forward use-dependence of a drug that is most effective at faster heart rates. This drug was in clinical trials in the late 1970s as an antidepressant and although it was safe, did not have the desired efficacy. It is now in clinical trials as a treatment for substance abuse. In neither of these trials were proarrhythmic tendencies noted and the ECGs in both sets of trials were unaffected. Because its properties are so favorable, ChanTest has filed a use patent on the drug for treatment of cardiac arrhythmias in general, and AF in particular. Given its very high affinity for hERG, a radioactive derivative can be used in high throughput displacement studies to test for non-cardiac drugs that may bind to hERG. Identifications of such drugs are of considerable importance for safety pharmacology. The specific aims of this proposal are to: 1) complete in vitro tests of the effects of the drug on other cardiac membrane currents ITo, IKs and IK1; 2) test the drug's efficacy in animal models of AF; 3) test the drug's safety in the cardiac muscle wedge preparation that is presently the best predictor of the potentially lethal ventricular arrhythmia torsade de pointes (TdP); and 4) characterize the drug congeners as tools for HTS displacement studies of drugs that bind hERG. After the drug passes the hurdles of the specific aims, ChanTest will file a 355(b)(2) NDA application with the FDA to go forward with the Phase II and III clinical trials. ChanTest believes that this drug will offer great relief to the many people who are debilitated by atrial fibrillation. [unreadable] [unreadable]